The major endeavor of this project is to characterize the pharmacological actions of the endogenous cannabinoids and identify commonalities and differences between delta/9-THC and the endogenous cannabinoids. We propose to continue the structure-activity relationship studies that have thus far resulted in potent and stable anandamide analogs. We intend to expand these SAR studies to gain a better understanding of how anandamide interacts with cannabinoid receptors. Analogs that are tetrahydrocannabinol/anandamide hybrids will provide a better understanding of structural features that are common for both of them. We also plan to prepare stable and potent analogs of 2-arachidonyl-glycerol which will greatly enhance our ability to fully characterize its pharmacological properties. These analogs will be evaluated for CB1 and CB2 receptor affinity, activation of 35/S-GTPgammaS binding, potency in the mouse tetrad assay, and mouse and rat drug discrimination. We will also pursue new leads in making derivatives of the CB1 selective antagonist SR141716A. While there is no question that anandamide interacts with the cannabinoid receptor and produces pharmacological effects similar to those of delta/9-THC, there are several differences in their pharmacological profile. We will undertake studies to determine whether these differences between anandamide and delta9-THC are due to pharmacokinetic or pharmacodynamics factors. Studies will be carried out to more clearly define the relationship between brain levels of anandamide and pharmacological effects it produces and to determine whether manipulation of its pharmacological effects with metabolic inhibitors is associated with concomitant changes in potency. Presently, it does not appear that annandamide is capable of producing either tolerance or dependence to the same extent as delta/9-THC. Several different strategies will be employed to determine whether anandamide can produce robust tolerance. The conditions under which tolerance develops to anandamide will be used to assess the dependence liability of anandamide. Development of dependence by anandamide would suggest a role for the endogenous system in addictive disorders, whereas failure of anandamide to produce dependence would provide further evidence that the actions of THC and anandamide are not identical. The development of stable and potent analogs of 2-arachidonyl-glycerol will allow us to evaluate the tolerance and dependence liability of this endogenous ligand as well. One additional means of assessing the THC-like properties of anandamide is the use of drug discrimination in mice and rats. Attempts will be made to train animals to higher and lower doses of THC which will increase the likelihood of uncovering THC-like responding by anandamide.